L13. Nano-structured, deferoxamine-eluting thin films significantly improve airway perfusion in translational animal models of lung transplantation

Objective:
Airway ischemia from bronchial devascularization during lung transplantation contributes to airway complications, infection, and development of bronchiolitis obliterans syndrome (BOS). Application of deferoxamine (DFO) has been shown to promote microvascular angiogenesis, which may be enhanced via sustained exposure. We studied the application of nanofiber-based thin films providing local and sustained delivery of DFO for mitigation of airway ischemia.
Methods:
Randomly aligned nanofiber-based films (~50 µm thick) were electrospun with polyglycolide (PGS; 12% w/v) and varied DFO concentrations (0%, 10%, 20% w/w) in hexafluoroisopropanol (Figure 1A-B). Tracheal devascularization and auto-transplantation of 4-5 ring segments of trachea were performed followed by no further treatment (operated controls) or application of non-drug loaded and DFO-loaded thin films to the anastomosis site in n=50 male Wistar rats (Figure 1C). Perfusion was assessed with laser speckle contrast angiography (LASCA) at baseline and at a 10-day terminal time point. Histology, immunohistochemistry, lectin angiographic staining, and real time polymerase chain reaction were used to study blood vessel regrowth. The nano-structured 10% DFO thin film was then applied in a tracheal patch allotransplant model in n=3 male and female pigs, from blood type and sex-matched donors, and compared to n=3 operated controls (Figure 1D). Perfusion was assessed at baseline and at a 14-day terminal endpoint, at which point bronchoscopy was performed. Tissue samples underwent molecular and histological assessment.
Results:
10% DFO thin films demonstrated sustained DFO release over 7 days in vitro. In rats, application of the 10% DFO film demonstrated the greatest improvement in perfusion via lectin staining (Figure 1E) (p<0.001) and LASCA (p<0.0001) (Figure 1F) compared to operated control. RT-PCR demonstrated significantly lower hypoxia-inducible factor alpha (HIF-1α) in DFO-treated tracheas (Figure 1G) (p<0.001). In the pig tracheal patch allotransplant model, the 10% DFO treatment group demonstrated lower airway perfusion loss than operated control (11.86.7% vs 41.513%).
Conclusions:
Sustained release of DFO from a nanofiber-based thin film applied to the allograft anastomosis site improves airway perfusion in airway ischemia and transplant models. This novel intervention may improve airway health post-lung transplantation and mitigate long-term complications of airway ischemia.

Aravind Krishnan (1), Mahdi Forouharshad (2), Elbert E. Heng (3), Alyssa Garrison (4), Vishnu Rompicharla (5), Shubham Patil (5), Arman Farazdaghi (5), Daniel Alnasir (6), Stefan Elde (4), Moeed Fawad (7), Brandon Guenthart (8), Laura Ensign (5), Y. Joseph Woo (9), Kunal Parikh (5), John MacArthur (10), (1) Stanford Hospital, Palo Alto, CA, (2) Johns Hopkins University School of Engineering, Baltimore, MD, (3) Stanford University Medical Center, Palo Alto, CA, (4) Stanford University, Palo Alto, CA, (5) Johns Hopkins University School of Medicine, Baltimore, MD, (6) Stanford University School of Medicine, Palo Alto, CA, (7) N/A, Palo Alto, CA, (8) Stanford University Medical Center, Stanford, CA, (9) Stanford University, Stanford, CA, (10) Stanford Hospital and Clinics, Menlo Park, CA

Thomas Waddell

Commentator

Thomas K. Waddell, MD, MSc, PhD, FRCSC, FACS

Dr. Waddell attended medical school at the University of Ottawa and completed his surgical and scientific training at the University of Toronto.  During his PhD studies, he received numerous honours for his research work including the Governor General’s Gold Medal and the Royal College Prize for Resident Research. He was appointed as Assistant Professor in 2000, promoted to Associate Professor in 2004, and was promoted to Full Professor in 2010.  He recently completed his term as the Pearson-Ginsberg Chair, Division of Thoracic Surgery, University of Toronto and Head of the Division of Thoracic Surgery at University Health Network/Toronto General Hospital.  He has earned numerous distinctions, including the Blalock Scholarship from the American Association for Thoracic Surgery, a CIHR New Investigator Award, a CFI New Opportunities Fund Award, the George Armstrong Peters Prize in the Department of Surgery, a Wightman-Berris Individual Teaching Award, and was recognized with the Elliott Chair in Transplantation Research in 2005 and the Thomson Chair in Translational Research in 2010.  In 2011, he received the highest research honour from the University of Toronto Department of Surgery, the Lister Prize. He has served as Chair of the Research Committee of the American Association for Thoracic Surgery as well as Chair of the Research Committee of the Thoracic Surgery Foundation for Research and Education. He was the founding CEO of XOR-Labs Toronto Inc, a medical devices development company commercializing organ perfusion from 2013 until its acquisition by Traferox Technologies in 2021.  His research focuses on the chronic shortage of donor lungs, especially stem cell and regenerative medicine approaches to lung disease.  He has published over 300 peer-reviewed scientific publications and has received over 7M in peer-reviewed research grants.

Aravind Krishnan

Abstract Presenter

Aravind Krishnan is a PGY4 in the Integrated Cardiothoracic Surgery Residency Program at Stanford University. He is in the laboratory of Dr. John W. MacArthur, and is interested in Heart and Lung Transplantation, and Mechanical Circulatory Support. His research encompasses basic, translational and clinical disciplines. Aravind is a graduate of the Johns Hopkins School of Medicine and the Johns Hopkins University. In his spare time he enjoys swimming as a former collegiate water polo player, and watching Formula 1. 

Specialties: Congenital, Thoracic